Panacos Pharmaceuticals, Inc. is collaborating with Professor K.H. Lee of The University of North Carolina at Chapel Hill to discover natural products and their derivatives that inhibit HIV replication and have novel mechanisms of action. During Phase I several lead compounds from this collaboration were analyzed and 4-methyl di-camphanoyl-khallactone (4-methyl DCK) was found to have suitable in vitro and in vivo characteristics for further development. This compound potently blocks replication of clinical HIV-1 isolates by inhibiting the fusion of virus to cells. 4-methyl DCK has a half-life of 2.5 hours following IV administration to rats, and metabolism studies in human and rat liver microsomes indicate it may have a longer half-life and greater oral bioavailability in humans. During Phase lI the pre-clinical development of 4-methyl DCK will be performed in order to file an IND for human clinical trials. This will include development of a formulation suitable for pre-clinical and clinical studies, scale-up of the synthesis method and completing animal pharmacokinetic and toxicology studies. In addition, the specific molecular mechanism of HIV-1 fusion inhibition by 4-methyl DCK will be analyzed and the potential for development of HIV-1 resistance examined. Finally, Phase I/II human clinical trials of 4-methyl DCK will be planned, focusing on assessment of the compound's pharmacokinetics, safety and antiviral activity in HIV-1-infected individuals. PROPOSED COMMERCIAL APPLICATION: The goal is to complete the pre-clinical development of 4-methyl DICK as a prelude to analyzing this compound's efficacy in human clinical trials. 4-methyl DCK has a different mechanism of action than approved HIV drugs and may offer considerable potential as a new drug candidate for use in combination therapy of HIV/AIDS.